Steric hindrance isosterism

For the characterization of the electronic and steric effects of substituents on the catalytic properties of tertiary aliphatic amines, Bogatkov et al. 71,72) proposed a correlation between the steric hindrance of R1R2R3N amines by means of the En(En) constants which are identical with steric constants ES(E9) according to Taft for isosteric hydrocarbon substrates R1 R2R3C. On this basis, they proposed the following linear correlation for the nucleophilic activity of amines ... 

Apparently we are dealing here with a classical isosteric series F, Cl, Br, I, but sensitive to steric hindrance in the para position. Probably what happens in vivo, is para-hydroxyla-tion of the benzene ring. The best candidate becomes then the para-fluoro compound, since it is not bulkier than the unsubstituted compound while being biostable. 

The process of constructing conformationally restricted analogs may fail for reasons other than steric hindrance or incorrect conformation. An enlightening example was encountered when the olefin isostere was used in place of the trans amide bond in the enzyme-bound conformation of CsA. As noted previously, the amide bond between positions 9,10 in CsA switches from cis in organic solution to trans in water and in the enzyme-bound conformation. When... 

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